Microenvironmental regulation of BRCA1 gene expression by c-Jun and Fra2 in premalignant human ovarian surface epithelial cells

Mol Cancer Res. 2013 Mar;11(3):272-81. doi: 10.1158/1541-7786.MCR-12-0395. Epub 2013 Jan 21.

Abstract

Reduced BRCA1 gene expression is common in the sporadic form of ovarian carcinoma. The spread of this highly lethal cancer often begins when tumor cell clusters are shed into the fluid of the abdominopelvic cavity such that they can float freely before seeding distant sites on the peritoneal walls and organs. Thus, the microenvironment that tumor cells find themselves in changes dramatically during these early shedding and floating stages of transperitoneal metastasis. To mimic this microenvironmental change in vitro, we released premalignant human ovarian surface epithelial cells from the substratum and forced them to cluster in suspension. Under these conditions, steady state levels of BRCA1 mRNA and protein fell significantly and the transcriptional activation state of the BRCA1 promoter was suppressed. Analysis of the promoter indicated that the previously identified "CRE" element located within the "positive regulatory region" (PRR) contributed to this suppression. More specifically, we show that the suppression was mediated, at least in part, by a suspension culture-driven decrease in the levels of two members of the AP1 transcription factor complex, c-Jun and Fra2, that bind to the CRE element. Therefore, a microenvironmental change that is manifested during the initial stages of ovarian carcinoma dissemination may, potentially, help suppress BRCA1 expression in sporadic tumors and thus promote their progression.

MeSH terms

  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Cell Line, Tumor
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Fos-Related Antigen-2 / genetics*
  • Fos-Related Antigen-2 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • JNK Mitogen-Activated Protein Kinases / genetics*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Staging
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Ovary / metabolism
  • Ovary / pathology*
  • Transcription Factors
  • Tumor Microenvironment

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • FOSL2 protein, human
  • Fos-Related Antigen-2
  • Transcription Factors
  • JNK Mitogen-Activated Protein Kinases